A major obstacle for viral disease treatment is viral persistence, which makes many current anti-rival therapies only temporality effective. Using HIV/AIDS as an example, nucleoside/nucleotide analog reverse transcriptase (RT) inhibitors, such as AZT, are the most commonly used drugs for inhibiting HIV reception. However, drug resistance generated by HIV mutations severely reduces the efficacy of those drugs. One reason for drug resistance against these chain terminators is the evolution of the HIV RT under selective pressure by the drug.
An approach, called “lethal mutagenesis” has recently been developed (Loeb et al., Proc. Natl. Acad. Sci. USA, 1999, 96, 1492-1497; Mullins et al., PLoS ONE, 2011, 6, e15135; Clay et al., Journal of the International Association of Physicians in AIDS Care, 2011, 10, 232-238; Harris et al., Antiviral Res. 2005, 67, 1-9). This approach involves nucleotide analogs that can be incorporated into the HIV genome and extended (they are not chain terminators) and increase the mutation rate of HIV. When the mutation rate of HIV is over its “error catastrophe limit,” the HIV will produce mostly non-viable progeny. Those nucleotide analogs are thus examples of lethal mutagens. The lethal mutagenesis approach has been shown to be safe by a drug candidate KP1212 (shown below, the active form of the pro-drug KP1461) in Phase I and II clinical trials and offers the possibility of treatment of the persistent population of HIV, which would become increasingly dominated by weak or non-viable viruses. Another molecule currently in clinical trials is compound T705, which is also known to work by lethal mutagenesis.
